The UCI ADRC Neuropathology Core links clinical evaluafions with definitive neuropathological diagnoses. Neuropathological criteria remain the definitive method for diagnosing Alzheimer's disease (AD), and the UCI ADRC follows the longitudinal cohort plus two unique pafient populafions: adults with Down syndrome and individuals over 90 years of age (i.e., 90+). Down syndrome represents the single most common cause of early-onset AD, whereas the 90+ cohort represents the later spectrum of aging, and has a high rate of conversion to demenfia. Both cohorts facilitate the study of the transition stages. The broad goal of the Neuropathology Core is to elucidate the underlying molecular mechanisms that define normal aging and the transition to MCI and the subsequent transition from MCI to AD/dementia. As part of its mission, the UCI Neuropathology Core also provides well-characterized tissues and reagents to basic scientists to sfimulate and facilitate research in AD, Down syndrome, other age-associated neurodegenerative diseases, and aging. Disseminafing fissues and reagents, which are well characterized both clinically and neuropathologically, helps advance the field by providing an important medium for evaluafing disease processes and for validating hypotheses in human samplesTo achieve these goals, the Neuropathology Core proposes 5 specific aims: (1) Obtain brain fissue from ADRC subjects (Longitudinal, Down syndrome, and 90+ Autopsy Cohorts) evaluated by the Clinical Core, (2) Convey an accurate and fimely neuropathological diagnosis to the Clinical, and Data Management and Statistics Cores, and to physicians and families of the deceased subjects, (3) Maintain an active Tissue Repository, (4) Develop Innovative Reagents and Animal Models to support demenfia research, with an emphasis on pepfides and anfibodies to different assembly states of Ap and novel AD transgenic mice, (5) Develop new approaches to study cellular and molecular mechanisms of AD by generafing induced pluripotent stem cells (iPSC).